Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database.

BACKGROUND: New sepsis and septic shock definitions could change the epidemiology of sepsis because of differences in criteria. We therefore compared the sepsis populations identified by the old and new definitions. METHODS: We used a high-quality, national, intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, from January 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old (Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsis and septic shock populations. RESULTS: From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3 sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. The extrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per 100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similar incidence, similar mortality and showed significant risk-adjusted improvements in mortality over time. Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2 septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severe sepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsis admissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock. CONCLUSIONS: In an ICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlap and much smaller septic shock population with improved predictive validity.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012

Objective: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7­9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO 2/FiO 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO 2/FI O 2<150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5­10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Cryoprecipitate transfusion: assessing appropriateness and dosing in trauma.

BACKGROUND: Originally developed for patients with congenital factor VIII deficiency, cryoprecipitate is currently largely used for acquired hypofibrinogenemia in the context of bleeding. However, scant evidence supports this indication and cryoprecipitate is commonly used outside guidelines. In trauma, the appropriate cryoprecipitate dose and its impact on plasma fibrinogen levels are unclear. OBJECTIVES: The aims were to evaluate (i) the appropriateness of cryoprecipitate transfusion in trauma and (ii) the plasma fibrinogen response to cryoprecipitate transfusion during massive transfusion in trauma. METHODS: Retrospective review (January 1998-June 2008) of indications, dose and plasma fibrinogen response to cryoprecipitate transfusion at a large teaching hospital. A fibrinogen of <1.0 g L(-1) within 2 and 6 h of transfusion was used for evaluating appropriateness. RESULTS: Ten thousand five hundred and forty cryoprecipitate units were transfused in 1004 patients. Thirty-seven percent and 31% were used in cardiac surgery and trauma, respectively. In 394 events in trauma, 238 (60%) and 259 (66%) were considered appropriate using the 2- and 6-h cut-off criteria, respectively. In patients who did not receive plasma components 2 h prior to cryoprecipitate, a dose of 8.7 (± 1.7) units caused a mean increase in fibrinogen levels of 0.55 (± 0.24) g L(-1), or 0.06 g L(-1) per unit. CONCLUSIONS: In our hospital, where transfusion guidelines are overseen by transfusion medicine specialists and technologists, and policies for rapid blood component and laboratory turnaround times exist, it is possible to achieve high rates of appropriateness for cryoprecipitate transfusion in trauma. The current recommended dose causes a modest increase in fibrinogen levels (0.55 g L(-1) ).

Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study.

Pulmonary arterial hypertension (PAH) is a disease of the small vessels in which there is a substantial increase in pulmonary vascular resistance leading to right ventricle failure and death. Invasive haemodynamic evaluation is mandatory not only for diagnosis confirmation but also to address prognosis and eligibility for the use of calcium-channel blockers through an acute vasodilator challenge. Noninvasive surrogate response markers to the acute vasodilator test have been sought. In the present study, the relationship between pulmonary artery distensibility, assessed using magnetic resonance imaging (MRI), and response to acute vasodilator tests was investigated. In total, 19 patients diagnosed with idiopathic PAH without any specific treatment were evaluated. Within a 48-h window after pulmonary artery catheterisation, patients underwent cardiac MRI. Cardiac index, calculated after the determination (invasively and noninvasively) of cardiac output, showed excellent correlation, as did right atrial pressure and right ventricle ejection fraction. Pulmonary artery distensibility was significantly higher in responders. A receiver operating characteristic curve analysis has shown that 10% distensibility was able to differentiate responders from nonresponders with 100% sensitivity and 56% specificity. The present findings suggest that magnetic resonance imaging and pulmonary artery distensibility may be useful noninvasive tools for the evaluation of patients with pulmonary hypertension.

Association between Stenotrophomonas maltophilia and lung function in cystic fibrosis.

BACKGROUND: Stenotrophomonas maltophilia (SM) is a Gram-negative non-fermenting bacteria cultured from the sputum of patients with cystic fibrosis (CF). To date, no information is available regarding the effect of this organism on lung function in CF. METHODS: A cohort study was conducted to assess the effect of SM on lung function among CF patients aged > or =6 years in the CF Foundation National Patient Registry from 1994 to 1999. Repeated measures regression was used to assess the association between SM and lung function. RESULTS: The cohort consisted of 20 755 patients with median age at entry of 13.8 years and median follow up time of 3.8 years; 2739 patients (13%) were positive at least once for SM and 18 016 (87%) were never positive. After adjusting for sex, height and age, patients with SM had a mean forced expiratory volume in 1 second which was 0.09 l less (95% CI 0.05 to 0.14) than those without SM. The mean rate of decline associated with SM positivity was 0.025 l/year (95% CI 0.012 to 0.037) but, after adjusting for confounders (sex, height, weight, intravenous antibiotic courses, hospital admissions, pancreatic insufficiency, and Pseudomonas aeruginosa and Burkholderia cepacia status), the mean rate of decline decreased to 0.008 l/year (-0.008, 95% CI -0.019 to 0.003). CONCLUSIONS: Although CF patients with SM have worse lung function at the time of positivity, no association was found between SM and increased rate of decline after controlling for confounders.

Understanding why we agree on the evidence but disagree on the medicine.

Despite the fact that physicians, nurses, and respiratory therapists share a common training in scientific evidence and frequently share a common understanding of the evidence, debates occur about the proper management of individual patients. Clinicians may interpret this as a failure of evidence-based medicine, when, in fact, evidence is only one of many factors that play a role in clinical decision-making. By clearly understanding the other factors that affect clinical decision making-prior beliefs about treatment effectiveness, patient and clinician values, and clinical expertise-clinicians can better understand which clinical disagreements are about scientific evidence and which are about other factors.

End-of-life care in the intensive care unit: a research agenda.

BACKGROUND: The intensive care unit (ICU) represents a unique clinical setting in which mortality is relatively high and the professional culture tends to be one of "rescue therapy" using technological and invasive interventions. For these reasons, the ICU is an important environment for understanding and improving end-of-life care. Although there have been consensus statements and review articles on end-of-life care in the ICU, there is limited evidence on which to base an assessment of best practices for providing high-quality end-of-life care in this setting. OBJECTIVE: To convene a Working Group of experts in critical care, palliative medicine, medical ethics, and medical law to address the question "What research needs to be done to improve end-of-life care to patients in the ICU?" METHODS: Participants were identified for membership in the Working Group by purposive sampling within the fields of critical care medicine and nursing, palliative medicine, and medical ethics; others were chosen to represent social work and hospital chaplains. Through a process of breakout and plenary sessions, the group identified important questions that need to be addressed in the areas of defining the problem, identifying solutions, evaluating solutions, and overcoming barriers. CONCLUSIONS: Outlining unanswered questions on end-of-life care in the ICU is a first step to providing the answers that will allow us to improve care to patients dying in the ICU. These questions also serve to focus clinicians and educators on the important areas for improving quality of care.

The etiology of community-acquired pneumonia at an urban public hospital: influence of human immunodeficiency virus infection and initial severity of illness.

In a prospective study, the etiology of community-acquired pneumonia (CAP) was investigated among consecutive patients admitted to an academic, urban public hospital in Seattle. The study population was uniquely young, was predominantly male, and had high rates of homelessness, cigarette smoking, alcoholism, injection drug use, and human immunodeficiency virus (HIV) infection. Leading causes of CAP among HIV-negative patients were aspiration, followed by Streptococcus pneumoniae, Legionella species, and Mycoplasma pneumoniae. Among HIV-positive patients, Pneumocystis carinii, Mycobacterium tuberculosis, S. pneumoniae, and M. pneumoniae were the most common etiologic agents. Severe CAP was associated with typical bacterial infections and aspiration pneumonia but not Legionella infection among HIV-negative patients and with Pseudomonas aeruginosa infections among HIV-positive patients. These findings emphasize the need to tailor empirical antibiotic therapy according to local patient populations and individual risk factors and highlight the importance of recognizing underlying HIV infection in patients who are hospitalized with CAP.

The family conference as a focus to improve communication about end-of-life care in the intensive care unit: opportunities for improvement.

The intensive care unit (ICU) represents a hospital setting in which death and discussion about end-of-life care are common, yet these conversations are often difficult. Such difficulties arise, in part, because a family may be facing an unexpected poor prognosis associated with an acute illness or exacerbation and, in part, because the ICU orientation is one of saving lives. Understanding and improving communication about end-of-life care between clinicians and families in the ICU is an important focus for improving the quality of care in the ICU. This communication often occurs in the "family conference" attended by several family members and members of the ICU team, including physicians, nurses, and social workers. In this article, we review the importance of communication about end-of-life care during the family conference and make specific recommendations for physicians and nurses interested in improving the quality of their communication about end-of-life care with family members. Because excellent end-of-life care is an important part of high-quality intensive care, ICU clinicians should approach the family conference with the same care and planning that they approach other ICU procedures. This article outlines specific steps that may facilitate good communication about end-of-life care in the ICU before, during, and after the conference. The article also provides direction for the future to improve physician-family and nurse-family communication about end-of-life care in the ICU and a research agenda to improve this communication. Research to examine and improve communication about end-of-life care in the ICU must proceed in conjunction with ongoing empiric efforts to improve the quality of care we provide to patients who die during or shortly after a stay in the ICU.

Clinical epidemiology of acute lung injury.

Acute lung injury (ALI) remains a serious threat to critically ill patients and continues to pose challenges to clinicians and investigators as they strive to better identify and treat these patients. Over 30 years of clinical and basic science investigations have led to a better understanding of the pathophysiology, risk factors, and prognosis of this entity but we still lack a "gold standard'' for its identification. The American-European Consensus Conference definition has helped in the effort to standardize the definition of ALI but is still fraught with difficulties in the application of criteria for the chest radiograph, hypoxemia, and left atrial hypertension. As further efforts are undertaken to better define ALI and to more accurately describe its incidence, it is critical that methodology to assess the accuracy and reliability of such definitions be utilized. This union of clinical epidemiology, clinical research, and basic science will not only better describe the population burden of ALI but will also better track the effect of current and future therapeutic interventions.

Implications of extubation delay in brain-injured patients meeting standard weaning criteria.

We hypothesized that variation in extubating brain injured patients would affect the incidence of nosocomial pneumonia, length of stay, and hospital charges. In a prospective cohort of consecutive, intubated brain-injured patients, we evaluated daily: intubation status, spontaneous ventilatory parameters, gas exchange, neurologic status, and specific outcomes listed above. Of 136 patients, 99 (73%) were extubated within 48 h of meeting defined readiness criteria. The other 37 patients (27%) remained intubated for a median 3 d (range, 2 to 19). Patients with delayed extubation developed more pneumonias (38 versus 21%, p < 0.05) and had longer intensive care unit (median, 8.6 versus 3.8 d; p < 0.001) and hospital (median, 19.9 versus 13.2 d; p = 0.009) stays. Practice variation existed after stratifying for differences in Glasgow Coma Scale scores (10 versus 7, p < 0.001) at time of meeting readiness criteria, particularly for comatose patients. There was a similar reintubation rate. Median hospital charges were $29,057.00 higher for extubation delay patients (p < 0.001). This study does not support delaying extubating patients when impaired neurologic status is the only concern prolonging intubation. A randomized trial of extubation at the time brain-injured patients fulfill standard weaning criteria is justifiable.

The effect of acute respiratory distress syndrome on long-term survival.

Despite a great deal of information about the risk factors, prognostic variables, and hospital mortality in the acute respiratory distress syndrome (ARDS), very little is known about the long-term outcomes of patients with this syndrome. We conducted a prospective, matched, parallel cohort study with the goals of describing the survival of patients with ARDS after hospital discharge and comparing the long-term survival of patients with ARDS and that of a group of matched controls. The study involved 127 patients with ARDS associated with trauma or sepsis and 127 controls matched for risk factor (trauma or sepsis) and severity of illness who survived to hospital discharge. Time until death was used as the outcome measure. Survival was associated with age, risk factor for ARDS, and comorbidity. There was no difference in the long-term mortality rate for ARDS patients and that of matched controls (hazard ratio for ARDS: 1.00; 95% confidence interval: 0.47 to 2.09) after controlling for age, risk factor for ARDS, comorbidity, and severity of illness. We conclude that if sepsis or trauma patients survive to hospital discharge, ARDS does not increase their risk of subsequent death. Older patients, patients with sepsis, and patients with comorbidities, regardless of the presence of ARDS, have a higher risk of death after hospital discharge. For the purposes of clinical prognosis and cost-effectiveness analysis, the long-term survival of patients with ARDS can be modeled on the basis of age, underlying risk factor for ARDS, and comorbidity.

Interobserver variability in applying a radiographic definition for ARDS.

CONTEXT: Acute lung injury (ALI) and ARDS are currently defined by the American-European Consensus Conference (AECC) definition criteria, which contain a radiographic criterion. The accuracy or reliability of this consensus radiographic definition has not been evaluated, and no radiographic definition of ALI-ARDS has been evaluated by a large international group of experts. OBJECTIVE: To study the interobserver variability in applying the AECC radiographic criterion for ALI-ARDS. DESIGN: Survey. PARTICIPANTS: A convenience sample of 21 experts selected from participants attending the 1997 Toronto Mechanical Ventilation Workshop and from members of the National Institutes of Health ARDS Network. OUTCOME MEASURES: Participants reviewed 28 randomly selected chest radiograph from critically ill, hypoxemic (PaO(2)/fraction of inspired oxygen ratio, < 300) patients and decided whether the radiograph fulfilled the AECC definition for ALI-ARDS. RESULTS: Interobserver agreement in applying the AECC definition for ALI-ARDS was moderate (kappa = 0.55; 95% confidence interval, 0.52 to 0.57). Thirteen radiographs (43%) showed nearly complete agreement (defined as 20 or 21 readers in agreement). Nine radiographs (32%) had more than or equal to five dissenting readers. The percentage of radiographs interpreted as consistent with ALI-ARDS by individual readers ranged from 36 to 71%. Participants commented that mild infiltrates, pleural effusions, atelectasis, isolated lower lobe involvement, radiographic technique, and overlying monitoring equipment posed the most difficulties. CONCLUSIONS: The radiographic criterion used in the current AECC definition for ALI-ARDS showed high interobserver variability when applied by expert investigators in the fields of mechanical ventilation and ARDS. This variability may result in differences in ALI-ARDS populations at different clinical research centers and may make it difficult for clinicians to apply the results of clinical trials to their patients. Modifications to the radiographic criterion or annotated reference radiograph may improve the reliability of future definitions for ALI-ARDS.

Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) frequently results in a fibroproliferative response that precludes effective alveolar repair. Transforming growth factor-alpha (TGF-alpha), a potent epithelial and mesenchymal cell mitogen, may modulate the response to lung injury. In this study, we determined whether bronchoalveolar lavage fluid (BALF) concentrations of TGF-alpha are increased during the first 2 wk after the onset of ARDS and, if so, whether increased TGF-alpha levels in lavage fluid are associated with increased levels of procollagen peptide III (PCP III), a biological marker of fibroproliferation, and with increased fatality rates. We enrolled 74 consecutive patients with ARDS prospectively identified on admission to the intensive care unit of a tertiary care hospital, and 11 patients with chronic interstitial lung disease. Thirteen healthy volunteers served as control subjects. TGF-alpha concentrations were measured in BALF recovered on Days 3, 7, and 14 after the onset of ARDS (total of 130 lavage samples). TGF-alpha was detected in the lavage fluid of 90% of patients with ARDS (67 of 74), and in 100% of patients with idiopathic pulmonary fibrosis (IPF) (10 of 10), but in none of 13 normal volunteers. At each day tested, the median lavage TGF-alpha level of patients with ARDS was significantly higher than that of normals. The overall fatality rate was 45% (33 of 74 patients). In a univariate analysis, the median TGF-alpha levels in nonsurvivors were 1.5-fold higher at Day 7 (p = 0.06) and 1.8-fold higher at Day 14 (p = 0.048). The fatality rate was 4 times higher (CI 1.6, 17.5) for patients with both increased lavage TGF-alpha and PCP III concentrations at Day 7 than for patients with low TGF-alpha and PCP III values, indicating a synergistic relationship between TGF-alpha and PCP III. We conclude that increased levels of TGF-alpha in BALF are common in patients with ARDS and that lavage TGF-alpha is associated with a marker of the fibroproliferative response in sustained ARDS.